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Proteome Sequencing and Analysis of Ophiocordyceps Sinensis At Zhang et al. BMC Genomics (2020) 21:886 https://doi.org/10.1186/s12864-020-07298-z RESEARCH ARTICLE Open Access Proteome sequencing and analysis of Ophiocordyceps sinensis at different culture periods Bo Zhang1,BoLi1, Xiao-Hui Men1, Zhe-Wen Xu1, Hui Wu2,3, Xiang-Tian Qin2,3, Feng Xu2,3, Yi Teng2,3, Shui-Jin Yuan2,3, Li-Qun Jin1, Zhi-Qiang Liu1* and Yu-Guo Zheng1 Abstract Background: Ophiocordyceps sinensis is an important traditional Chinese medicine for its comprehensive active ingredients, such as cordycepin, cordycepic acid, and Cordyceps polysaccharide. O. sinensis zjut, a special strain isolated from O. sinensis, has similar pharmacological functions to wild O. sinensis. Currently, O. sinensis with artificial cultivation has been widely studied, but systematic fundamental research at protein levels has not been determined. Results: Proteomes of O. sinensis zjut at different culture periods (growth period, 3rd day; pre-stable period, 6th day; and stable period, 9th day) were relatively quantified by relative isotope markers and absolute quantitative technology. In total, 4005 proteins were obtained and further annotated with Gene Ontology, Kyoto Encyclopedia of Genes and Genomes database. Based on the result of the annotations, metabolic pathways of active ingredients, amino acids and fatty acid were constructed, and the related enzymes were exhibited. Subsequently, comparative proteomics of O. sinensis zjut identified the differentially expressed proteins (DEPs) by growth in different culture periods, to find the important proteins involved in metabolic pathways of active ingredients. 605 DEPs between 6d- VS-3d, 1188 DEPs between 9d-VS-3d, and 428 DEPs between 9d-VS-6d were obtained, respectively. Conclusion: This work provided scientific basis to study protein profile and comparison of protein expression levels of O. sinensis zjut, and it will be helpful for metabolic engineering works to active ingredients for exploration, application and improvement of this fungus. Keywords: O. sinensis zjut, Proteome, Differentially expressed proteins, Active ingredients Background immunomodulatory effects, antioxidant activity and Ophiocordyceps sinensis is an important traditional anti-cancer [4, 5]. However, due to high demand and in- Chinese medicine and healthy food in China [1–3]. Pre- sufficient supply for wild O. sinensis, the medicinal value vious studies have revealed that active ingredients of O. development has been seriously limited [6, 7]. Recently, sinensis, including D-mannitol, cordycepin, purine nu- several strains that isolated from wild O. sinensis have cleotides and polysaccharide, have various pharmaco- similar pharmacological functions to wild O. sinensis [8], logical functions, such as adaptogenic activity, representing an useful alternative for production. More- over, new potential drugs and active compounds derived * Correspondence: [email protected] from natural sources have been screened as effective dis- 1 Key Laboratory of Bioorganic Synthesis of Zhejiang Province, College of ease treatment from Hirsutella sinensis, which is the po- Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China tential anamorph of O. sinensis. The antitumor activity Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang et al. BMC Genomics (2020) 21:886 Page 2 of 10 of H. sinensis mycelium was found as seen in studies on functions directly at the protein level and tried to illu- human tissue, including prostate (PC3), breast (MCF7), minate the synthesis mechanism of active ingredients in hepatocellular (HepG2, Hep3B) and colorectal (HT-29) this study. [9, 10]. Previous studies have revealed the active ingredi- In this study, proteomes of the O. sinensis zjut at dif- ents of artificially-cultivated O. sinensis had extensive ferent culture periods were relatively quantified by medicinal value for human health, such as anti-fatigue iTRAQ together with two-dimensional liquid chroma- activity [11], immunomodulatory activity [12], antioxi- tography tandem mass spectrometry (LC-MS/MS). dant activity [13] and anti-obesity effects [14]. Further- Large-scale identification and different expression ana- more, the productions of active ingredients in H. sinensis lysis of the proteins were performed, and metabolic by submerged fermentation were promoted and satisfy- pathways were constructed, especially active ingredients. ing on the basis of genetic study [15–17]. Proteomics is the large-scale study of proteins, and it can be divided into the areas of large-scale identification Results of proteins and their post-translational modifications, Protein profiling and iTRAQ quantification comparison of protein expression levels, and protein- In order to obtain the overview of the O. sinensis zjut protein interactions [18]. In previous studies, biochem- proteome, the protein samples were prepared from the ical methods have been widely used to study proteome, mycelium at different culture periods (3d, 6d and 9d) including polyacrylamide gel electrophoresis (PAGE), and relatively quantified by iTRAQ. A total of 371,999 two-dimensional electrophoresis (2-DE) liquid chroma- spectra were generated and 4005 proteins included 22, tography, surface-enhanced laser desorption ionization- 202 peptides were identified (with 1% FDR) (Supplemen- time of flight-mass spectrometry (SELDI-TOF-MS), and tary information 3: Table S2). GO analysis of total pro- matrix-assisted laser desorption ionization-time of flight- teins was based on biological process, cellular mass spectrometry (MALDI-TOF-MS) [19, 20]. Re- component and molecular function, and all proteins cently, with the ability to carry out relative (or absolute) were classified into 41 functional groups (Fig. 1). Bio- quantification in up to eight phenotypes, isobaric tags logical processes were associated with the following brief for relative and absolute quantification (iTRAQ) have pathways: metabolic process (29.27%), cellular process caught the attention of proteomics community [21, 22]. (25.99%) and single-organism process (17.72%); cellular iTRAQ-based proteomics has been used in studying components were assigned to the following cellular com- secretome, plasma membrane proteome, and intracellu- partments: cell (24.98%), cell part (24.98%) and organelle lar proteome [22–24]. (15.73%); The most highly enriched molecular functions Genome sequence of O. sinensis has been reported, were binding (48.34%), followed by catalytic activity which revealed the pathogenic mechanism during life (40.73%). Moreover, the proteins were further classified cycle [25]. Then, transcriptomes of H. sinensis at diffi- into 24 functional categories using COG classifications dent culture periods have been sequenced and analyzed (Fig. 2). The largest group category was found to have to describe metabolic pathway and infection mechanism general functions only (18.68%), followed by transla- [26]. Meanwhile, the comparative proteomic has shown tion, ribosomal structure and biogenesis (9.00%), and a snapshot proteome profile and revealed the similarity posttranslational modification, protein turnover, chap- of the proteins and metabolites composition between erones (7.72%). Only a small fraction of the protein naturally- and artificially-cultivated of O. sinensis [27]. was functionally related to the categories of cell mo- Dong et al studied the dynamic polymorphic alterations tility (0.22%) and nuclear structure (0.06%). About among differentially expressed proteins of multiple in- 2.95% of the identified proteins (94 proteins) were re- trinsic fungi in the caterpillar body and stroma of nat- lated to secondary metabolites biosynthesis, transport ural O. sinensis during maturation, and the results and catabolism. revealed there were the apparent proteomic polymorph- In this study, 6d-VS-3d, 9d-VS-3d, and 9d-VS-6d ism dissimilarity of these organisms to support the inte- were set as comparison groups. Corresponding pro- grated micro-ecosystem hypothesis for natural O. teins, exhibiting a greater than 1.2-fold change and sinensis [28]. In addition, there were some non- Q-value less than 0.05, were defined as differentially quantitative studies about the proteomics of O. sinensis expressed proteins. Ultimately, 605 DEPs (340 up- [27–30]. In fact, without the complement of proteomics, regulated proteins and 265 down-regulated proteins) only genome and transcriptome sequences are not suffi- between 6d-VS-3d,
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